An early event of retinoic acid (RA) action to promote differentiation of embryonal carcinoma (EC) stem cells is to sensitize the cells to cyclic AMP by elevating cytosolic and membrane-associated cyclic AMP-dependent protein kinase (cAMP-PK) activities. Studies now indicate that RA treatment of F9 stem cells causes a rapid (within 1 hr) and pronounced (approximately 50%) decrease in the RI and RII regulatory subunits, and in cAMP- PK activity, at the nucleus. This decrease in nuclear cAMP-PK activity may be an early event of retinoid action to mediate eventual cellular differentiation. Studies also have addressed the mechanism(s) by which retinoids act to antagonize the effects of phorbol ester tumor promoter (TPA). Treatment of PYS cells with TPA causes a rapid (within )0 min) increase in cAMP-PK activity in thc cytosol and a concomitant decrease in this activity associated with membranes. Addition of RA simultaneously with TPA completely blocks the TPA effect on cAMP-PK. Studies have shown that cAMPPK as well as the levels of the RI and RII regulatory subunits, are decreased in fibroblasts derived from skin biopsy samples of psoriatic adult patients. Retinoic acid treatment of psoriatic fibroblasts in cell culture induces a pronounced increase (within 3-4 hrs) in the amount of the Ri and RII subunits and in cAMP-PK activity to levels comparable to that found in normal human fibroblasts. This in vitro effect of retinoids on cAMP-PK in psoriatic fibroblasts may explain, at least in part, some of the in vivo therapeutic effects of retinoids.